Am. J. Hum. Genet. 64:563–569, 1999

Novel Locus for Autosomal Dominant Hereditary Spastic Paraplegia, on 8q Peter Hedera,1 Shirley Rainier,1 David Alvarado,1 Xinping Zhao,1 Jeffery Williamson,1 Brith Otterud,3 Mark Leppert,3 and John K. Fink1,2 1Department of Neurology, University of Michigan, and 2Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Ann Arbor; and 3Howard Hughes Medical Institute and the Eccles Institute of Human Genetics, University of Utah, Salt Lake City

Summary 1975; Holmes and Shaywitz 1977; Boustany et al. 1987; Keppen et al. 1987; McKusick 1988; Baraitser 1990; Hereditary spastic paraplegia (HSP) is a clinically and Scheltens et al. 1990; Harding 1993; Polo et al. 1993). genetically heterogeneous group of disorders character- (See reviews by the Hereditary Spastic Paraplegia Work- ized by insidiously progressive spastic weakness in the ing Group [Fink et al. 1996] and Fink [1997]). HSP is legs. Genetic loci for autosomal dominant HSP exist on classified according to both the mode of inheritance (au- 2p, 14q, and 15q. These loci are excluded tosomal dominant, autosomal recessive, and X linked) in 45% of autosomal dominant HSP kindreds, indicating and whether progressive spasticity occurs in isolation the presence of additional loci for autosomal dominant (“uncomplicated HSP”) or with other neurological HSP. We analyzed a Caucasian kindred with autosomal abnormalities (“complicated HSP”), including optic dominant HSP and identified tight linkage between the neuropathy, retinopathy, extrapyramidal disturbance, disorder and microsatellite markers on chromosome 8q dementia, ataxia, icthyosis, mental retardation, and (maximum two-point LOD score 5.51 at recombination deafness. The major neuropathological feature of au- fraction 0). Our results clearly establish the existence of tosomal dominant, uncomplicated HSP is axonal de- a locus for autosomal dominant HSP on chromosome generation that is maximal in the terminal portions of 8q23-24. Currently this locus spans 6.2 cM between the longest descending and ascending tracts (crossed and D8S1804 and D8S1774 and includes several potential uncrossed corticospinal tracts to the legs and fasciculus candidate . Identifying this novel HSP locus on gracilis, respectively) (Schwarz and Liu 1956; Behan and chromosome 8q23-24 will facilitate discovery of this Maia 1974; Harding 1993) Spinocerebellar fibers are HSP , improve genetic counseling for families with involved to a lesser extent. linkage to this locus, and extend our ability to correlate Each genetic type of HSP (autosomal dominant, re- clinical features with different HSP loci. cessive, and X-linked) is genetically heterogeneous (see review by Fink et al. [1996]). Loci for autosomal dom- inant HSP are present on chromosomes 2p, 14q, and 15q (Hazan et al. 1993, 1994; Figlewicz et al. 1994; Introduction Hentati et al. 1994; Fink et al. 1995a, 1995b; Gispert et al. 1995; Lennon et al. 1995). Among the 33 HSP The hereditary spastic paraplegias (HSP) (MIM 182600, kindreds reported by the Hereditary Spastic Paraplegia MIM 182601, MIM 270800, 312920, and MIM Working Group (Fink et al. 1996), linkage to chromo- 600363) are a group of clinically and genetically diverse some 2p was the most common, being observed in 15 disorders characterized by progressive, usually severe, (45%) of 33 kindreds. Two kindreds (6%) were linked lower-extremity spasticity (Rhein 1914; Philipp 1949; to chromosome 14q. Linkage to chromosome 15q (Fink Schwarz and Liu 1956; Roe 1963; Cartlidge and Bone et al. 1995b) was observed in 1 (3%) of 33 kindreds. 1973; Behan and Maia 1974; Skre 1974; Sutherland Known HSP loci on chromosomes 2p, 14q, and 15q were excluded in 15 of 33 autosomal dominant HSP Received September 28, 1998; accepted for publication November kindreds. The exclusion of known loci in 45% of au- 30, 1998; electronically published January 21, 1999. tosomal dominant HSP kindreds indicates the presence Address for correspondence and reprints: Dr. John K. Fink, 5214 of additional loci for autosomal dominant HSP. We eval- CCGCB, 1500 East Medical Center Drive, Ann Arbor, MI 48109- uated a white kindred with uncomplicated, autosomal 0940. E-mail: jkfi[email protected] ᭧ 1999 by The American Society of Human Genetics. All rights reserved. dominant HSP and excluded linkage to known HSP loci. 0002-9297/99/6402-0027$02.00 We performed a genomewide search for a novel HSP

563 564 Am. J. Hum. Genet. 64:563–569, 1999 locus in this family and observed tight linkage of the and had no evidence of similar neurological disorders in disorder to a group of microsatellite markers loci on their families. We did not include in our analysis either chromosome 8q. subjects for whom the diagnosis was uncertain or sub- jects considered “at risk” of developing HSP (i.e., asymp- Subjects, Material, and Methods tomatic subjects with normal neurological examinations who were !50 years of age). Subjects We examined 21 members of a nonconsanguineous Genotyping and Linkage Analysis North American kindred of German descent (fig. 1). One DNA was extracted from peripheral blood leukocytes additional subject (subject V-13; see fig. 1) was inter- as described elsewhere (Bell et al. 1981). Microsatellite viewed but was not examined; medical records from his DNA polymorphisms were amplified by PCR, according referring neurologist were reviewed. Pedigree informa- to standard procedures. Amplifications were performed tion was obtained from many relatives. Informed con- in 25-ml vols in 96-well trays, by Coy and M.J. Research sent was obtained from each subject, as specified by the thermocyclers, for 35 cycles. One primer was labeled University of Michigan institutional review board. Sub- with [g32P]-ATP, by means of T4 polynucleotide kinase. jects were diagnosed according to published criteria Amplified DNA was electrophoresed on 7% polyacryl- (Fink et al. 1996), at the time of blood collection and amide/6M urea-formamide gels, and alleles were scored prior to genotyping. Deceased subjects were diagnosed on the basis of autoradiographs. as “affected” or “unaffected” on the basis of the de- Two-point linkage analyses were performed by the scriptions of at least two relatives. Age at onset of symp- MLINK subroutine of the LINKAGE program (Lathrop toms was obtained by interviewing the living affected et al. 1985), with an autosomal dominant model of dis- subjects. ease inheritance and with a disease-allele frequency of We performed genetic-linkage analysis, using 15 living .001. We assigned a genetic penetrance of .90 for LOD- affected subjects, 4 living unaffected subjects, and 3 score calculations. spouses of descendants. Marrying-in spouses were Marker-allele frequencies were not calculated from asymptomatic, had normal neurological examinations, data for this family, since only three unrelated spouses

Figure 1 Kindred with HSP linked to chromosome 8q23-24 (SPG8) Hedera et al.: Hereditary Spastic Paraplegia on 8q 565 were available. Instead, LOD scores were calculated with Table 1 marker-allele frequencies assumed to be equal. The Exclusion of Linkage to Known Autosomal Dominant HSP Loci LINKMAP program of LINKAGE, used for multipoint HSP LOCUS linkage analysis, utilized published locations (Marshfield TWO-POINT LOD SCORE AT v ϭ AND MARKER Medical Research Foundation) of markers D8S1084, (PENETRANCE) .001 .05 .1 .2 .3 .4 D8S1799, D8S1179, D8S266, D8S1461, and D8S1774. 2p: D2S352 (.90) Ϫ5.45 Ϫ1.72 Ϫ.99 Ϫ.41 Ϫ.18 Ϫ.07 Results D2S367 (.90) Ϫ1.22 .26 .34 .27 .16 .07 14q: Clinical Analysis D14S269 (.90) Ϫ1.94 Ϫ.33 Ϫ.12 .01 .03 .01 D14S306 (.90) Ϫ6.70 Ϫ2.24 Ϫ1.39 Ϫ.64 Ϫ.31 Ϫ.12 HSP was diagnosed in 15 living subjects who devel- D14S288 (.90) Ϫ4.17 Ϫ.97 Ϫ.51 Ϫ.17 Ϫ.06 Ϫ.02 oped insidiously progressive gait disturbance at age 15q: 22–60 years (mean age 37.3 years; SD 12.2 years). Neu- D15S122 (.90) Ϫ2.12 Ϫ.53 Ϫ.32 Ϫ.15 Ϫ.07 Ϫ.02 Ϫ Ϫ rological examination of affected subjects demonstrated D15S128 (.908) 1.64 .06 .10 .12 .06 .02 D15S156 (.90) .44 .39 .33 .21 .11 .04 spastic diplegic gait disturbance (ranging from mild to D15S165 (.90) Ϫ2.57 Ϫ.87 Ϫ.56 Ϫ.26 Ϫ.11 .04 profound), frank corticospinal-tract deficits in the lower extremities (including spasticity, grade 4 hyperreflexia, and extensor plantar responses), weakness of hip flexion and D2S1787 gave LOD scores of Ϫ10.20 and Ϫ17.17, and ankle dorsiflexion, diminished vibratory sensation respectively, atv ϭ 0 and of Ϫ2.20 and Ϫ3.69, respec- in the feet, and, often, pes cavus. Mild terminal dys- tively, atv ϭ .10 ; D10S1739 and D10S159 gave LOD metria on finger-to-nose testing was noted in several sub- scores of Ϫ3.63 and Ϫ10.82, respectively, atv ϭ 0 and jects. There was no muscle wasting, with the exception of Ϫ1.34 and Ϫ2.68, respectively, atv ϭ .05 ; D18S870 of mild muscle atrophy, which, when present, was noted and D18S812 gave LOD scores of Ϫ4.03 and Ϫ3.55, in the shins of subjects in wheelchairs. Bladder distur- respectively, atv ϭ 0 and of Ϫ0.74 and Ϫ0.38, respec- bance (urgency and incontinence) was present in 7 of tively, atv ϭ .05 . These data indicated that positive LOD 15 affected subjects. scores for these single microsatellite markers were simply We observed one instance of probable incomplete ge- random associations observed in a relatively small netic penetrance. Subject V-13 (fig. 1) is unequivocally kindred. affected with insidiously progressive, severe spastic para- plegia, which began at age 23 years. His mother (subject Linkage to Chromosome 8q IV-15; see fig. 1), who is asymptomatic and whose neu- rological examination at age 60 years demonstrated only We observed linkage of the disorder to a group of subtle decreased stride length, is either nonpenetrant or marker loci mapped to chromosome 8q (table 2). Under presymptomatic. the assumption that genetic penetrance was .90, the maximum two-point LOD score was 5.51 (v ϭ 0 ) Exclusion Analysis for D8S1179 (CHLC.GATA 7G06.P6384). Three ad- ditional markers—namely, D8S1138 (CHLC.GATA We tested linkage to microsatellite polymorphisms lo- 50B06.P15277), D8S1799 (AFM283xb5), and cated at known autosomal dominant HSP loci on chro- D8S1461 (CHLC.ATA 42A09.P34343)—also yielded mosomes 2p, 14q, and 15q. We observed negative LOD two-point LOD scores 13.0 (table 2). Marker D8S266 scores for markers flanking and within these loci (table (AFM151ye3) yielded a two-point LOD score of 2.94 1). These data indicated that the disorder in this kindred atv ϭ 0 . A significantly positive two-point LOD score was not linked to these known HSP loci. was obtained for D8S1138 (LOD score 3.6 atv ϭ 0 ), although this marker could not be located precisely on Genomewide Search for a Novel HSP Locus the same genetic map of this region (Marshfield Medical We then undertook genomewide genetic-linkage anal- Research Foundation) on which the other markers were ysis to identify the novel HSP locus in this family. We located. However, two-point LOD-score analysis dem- analyzed 284 microsatellite polymorphisms, spaced onstrated that this marker (D8S1138) had no recom- 5–20 cM throughout the genome, for linkage with the binations with markers D8S266 and D8S1461, both of disorder in this HSP kindred. We observed positive LOD which were located in the nonrecombinant disease scores for individual markers located on chromosomes haplotype. 2, 10, and 18: D2S1391, 3.11 (v ϭ 0 ); D10S1709, 2.77 As noted above, we observed one individual (subject (v ϭ 0 ); D18S380, 2.04 (v ϭ 0 ). However, we observed IV-15; see fig. 1) who is either presymptomatic or non- significantly negative LOD scores for markers as close penetrant. Therefore, we repeated two-point linkage as 1–2 cM from each of these loci. For example, D2S364 analysis, assigning genetic penetrances .80 and .70 (table 566 Am. J. Hum. Genet. 64:563–569, 1999

Table 2 Results of Two-Point Linkage Analysis for Microsatellite Polymorphisms on Chromosome 8q23-24

TWO-POINT LOD SCORE AT v ϭ

MARKER AND PENETRANCE .001 .05 .10 .20 .30 .40 D8S1804 (AFM312yg5): .9 Ϫ1.79 1.28 1.50 1.30 .85 .38 .8 Ϫ1.64 1.36 1.56 1.33 .87 .38 .7 Ϫ1.54 1.43 1.61 1.35 .87 .38 D8S1138 (CHLC.GATA 50B06.P15277): .9 3.60 3.19 2.27 1.92 1.11 .45 .8 3.69 3.26 2.82 1.94 1.12 .45 .7 3.75 3.30 2.85 1.96 1.13 .45 D8S1179 (CHCL.GATA 7G06.P6384): 0.9 5.51 4.92 4.33 3.14 1.95 .85 .8 5.39 4.83 4.25 3.07 1.91 .84 .7 5.29 4.73 4.17 3.01 1.87 .82 D8S1799 (AFM283xb5): .9 3.28 2.91 2.53 1.77 1.07 .47 .8 3.48 3.08 2.68 1.88 1.13 .49 .7 3.28 2.89 2.50 1.74 1.04 .45 D8S266 (AFM151ye3): .9 2.94 2.64 2.33 1.67 1.02 .46 .8 3.11 2.78 2.43 1.73 1.06 .47 .7 3.24 2.88 2.52 1.78 1.08 .46 D8S1461 (CHLC.ATA 42A09.P34343): .9 3.09 2.65 2.20 1.37 .67 .19 .8 3.28 2.81 2.34 1.46 .73 .22 .7 2.88 2.45 2.03 1.26 .62 .18 D8S1774 (AFMb321wc1): .9 2.30 3.47 3.25 2.47 1.58 .71 .8 2.24 3.40 3.18 2.42 1.54 .69 .7 2.19 3.34 3.12 2.37 1.50 .67

2). Even at a lowered penetrance of .70, three markers Discussion with LOD scores 13.0 (v ϭ 0 ) remained statistically significant (table 2). The LOD score for D8S266 Our data establish the existence of a locus for auto- (AFM151ye3) increased from 2.94 (v ϭ 0 ) to 3.24 somal dominant, uncomplicated HSP, in the telomeric (v ϭ 0 ) when penetrance was reduced from .90 to .70. region of chromosome 8q. Previous physical mapping The most informative marker, D8S1179 (CHLC.GATA (NIH/CEPH Collaborative Mapping Group 1992) of the 7G06.P6384), did not change substantially when LOD microsatellite markers allows us to assign the HSP locus scores were calculated at a penetrance of either .90 (LOD to chromosome 8q23-24. At present, our data localize score 5.51 atv ϭ 0 ) or .70 (LOD score 5.29 atv ϭ 0 ). this region to a 6.2-cM interval between D8S1804 and The genotypes for all markers with no recombination D8S1774 (fig. 2). and the two adjacent flanking markers showing obligate The Genome Database designations for HSP (“spastic recombinants at D8S1804 and D8S1774 are shown with gait” [SPG]) loci are “SPG1” (X linked), “SPG2”(X the pedigree in figure 1. linked), “SPG3” (chromosome 14q, autosomal domi- Multipoint linkage analysis was performed for the dis- nant), “SPG4” (chromosome 2p, autosomal dominant), ease locus and two adjacent markers at a time, sequen- “SPG5” (chromosome 8q, autosomal recessive), and tially, for all markers from D8S1799 to D8S266 “SPG6” (chromosome 15q, autosomal dominant) (see (D8S1799, D8S1461, D8S1179, and D8S266). Pub- review by Fink et al. [1996]). It would be appropriate lished distances between these markers were obtained to designate the recently identified locus from Marshfield Medical Research Foundation (fig. 2). for autosomal recessive HSP as “SPG7” (De Michele et A genetic penetrance of .90 was used for these calcu- al. 1998). We propose that the chromosome 8q23-24 lations. Multipoint linkage analysis produced a maxi- locus for autosomal dominant, uncomplicated HSP be mum LOD score of 7.26, at D8S1179. designated “SPG8.” Hedera et al.: Hereditary Spastic Paraplegia on 8q 567

described in HSP (Fink et al. 1996). For example, Niel- sen et al. (1997, 1998) reported genetic anticipation in autosomal dominant uncomplicated HSP kindreds in which the disorder was linked to chromosome 2p. Fur- thermore, they also observed an expanded trinucleotide repeat that segregated with the disorder in these kindreds (Nielsen et al. 1997). We determined age at onset of symptoms by inter- viewing the living affected subjects. Estimated age at onset of symptoms in deceased subjects was not in- cluded, because this information was considered inac- curate. Only three sets of living affected parents and their living affected children were available for which we could compare age at onset of symptoms in succeeding generations. Subject IV-13 (fig. 1) had symptom onset later (age 60 years) than his children (age at onset of symptoms in subjects V-9, V-10, and V-12 was 40, 38, and 40 years, respectively). In contrast, the age at onset of symptoms (28 years) in subject V-6 was similar to that (age 30 years) in her daughter (subject VI-1). Sim- Figure 2 SPG8 locus on chromosome 8q23-24: genetic map. ilarly, the age at onset of symptoms (38 years) in subject Locations of genetic markers (Kosambi distances [in cM] are given in V-10 was similar to that (age 30 years) in his son (subject parentheses) were obtained from Marshfield Medical Research Foun- VI-2). Thus, although we have only limited data, we did dation Center for Medical Genetics. not observe a consistent trend toward progressively younger age at onset of symptoms in succeeding gen- With identification of autosomal dominant HSP loci erations in this family. on chromosomes 2p, 8q, 14q, and 15q, it is possible to Analysis of candidate genes is an important approach compare phenotypes in families in which the disorder is toward discovery of both the SPG8 gene and genes re- linked to each of these loci and in those families in which sponsible for other types of HSP. The distribution of each of these loci is excluded. The disorder in the chro- axonal degeneration to the terminal portions of the long- mosome 8q–linked family that we studied was insidi- est CNS axons raises the possibility that genes involved ously progressive and very severe. Ten of 15 subjects in neurotrophic regulation, maintenance of axonal cy- 140 of age required wheelchairs. The average age at toskeleton, or axoplasmic flow could be involved. The onset of symptoms in this family (37.3 years) was later defect is quite selective. Pathological changes are con- than that in the single reported chromosome 15q–linked fined to central—not peripheral—axons. family (22.5 years [Fink et al. 1995a]) but was similar Recently, mutations in a novel mitochondrial metal- to both that in the chromosome 14q–linked family re- loprotease gene (paraplegin) on chromosome 16 were ported by Hazan et al. (1993) (average age at onset of identified in subjects with autosomal recessive HSP (Cas- symptoms 31.6 years) and that in the four chromosome ari et al. 1998). Evidence of mitochondrial disturbance 2p–linked families reported by Nance et al. (1998) (av- was provided by abnormal-appearing mitochondria erage age at onset of symptoms 35 years). (“ragged red fibers”) in the muscle biopsy from two We could discern no clinical features that distin- patients. Although Casari et al. (1998) found evidence guished between the disorder in this chromosome of three structurally related paraplegin-like genes on 8q–linked HSP family and those reported in uncompli- chromosomes 4, 10, and 16, there was no evidence of cated autosomal dominant HSP families with linkage to a homologous gene on chromosome 8. Nonetheless, chromosomes 2p, 14q, or 15q (Fink et al. 1996). This both the discovery of the paraplegin gene and evidence observation suggests that the different abnormal gene of mitochondrial disturbance in one form of autosomal products responsible for these disorders participate in a recessive HSP provide important insight into biochem- common biochemical cascade that results in a similar ical pathways that, if disturbed, could result in HSP’s pattern of CNS degeneration. Alternatively, phenotypic selective axonal degeneration. similarity of HSP that links to different loci could be Analysis of X-linked HSP also suggests a potential explained by the presence of a family of structurally class of candidate genes for autosomal dominant HSP. related genes that are present at each HSP locus. Cambi et al. (1995) found a missense mutation in the Although not common, genetic anticipation has been proteolipoprotein (PLP) gene coding sequence in affected 568 Am. J. Hum. Genet. 64:563–569, 1999 males of one family but not in a second family. Muta- Genome Database, http://gdbwww.gdb.org (for HSP genes/ tions in the two PLP exons also were identified in af- loci) fected subjects from another, unrelated kindred with un- Marshfield Medical Research Foundation, http://www complicated X-linked HSP (Dube et al. 1997). Thus, in .marshmed.org/genetics (for marker locations) these families, uncomplicated X-linked HSP is allelic to Online Mendelian Inheritance in Man (OMIM), http:// www.ncbi.mlm.nih.gov/Omim (for HSPs [MIM 182600, both complicated X-linked HSP (Zatz et al. 1976; Ko- MIM 182601, MIM 270800, MIM 312920, and MIM bayashi et al. 1994) and Pelizaeus-Merzbacher disease, 600363]) since they all result from PLP-gene mutations. Uncom- plicated HSP is characterized by progressive axonal de- References generation, rather than by the primary dysmyelination characteristic of Pelizeaus-Merzbacher disease. None- Baraitser M (1990) Spastic paraplegia/HSP. In: Motulsky AG, theless, the presence of PLP-gene mutations in X-linked, Bobrow M, Harper PS, Scriver C (eds) The genetics of neu- uncomplicated HSP indicates that consideration of po- rological disorders. Oxford University Press, New York, pp tential candidate genes should include those involved in 275–290 myelin synthesis. Behan W, Maia M (1974) Strumpell’s familial spastic para- We searched the Genome Database for genes mapped plegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 37:8–20 to the SPG8 locus (D8S1804–D8S1774) on chromo- Bell GJ, Karam JH, Rutter WJ (1981) Polymorphic DNA re- some 8q23-24. Interesting and potential candidate genes gion adjacent to the 5 end of the human insulin gene. Proc among this list include KCNQ3 (the potassium-channel Natl Acad Sci USA 78:5759–5763 gene implicated in benign familial neonatal convulsions); Boustany R-MN, Fleischnick E, Alper CA, Marazita ML, syntrophin beta 1 (SNT2B1), a widely expressed dys- Spense MA, Martin JB, Kolodny EH (1987) The autosomal trophin-associated ; protein kinase (PTK2); phos- dominant form of “pure” familial spastic paraplegia. Neu- pholipase, A2 like (PLA2L); phosphodiesterase I/nu- rology 37:910–915 cleotide pyrophosphatase 2 (PDNP2); and plectin 1 Cambi F, Tartaglino L, Lublin FD, McCarren D (1995) X- (PLEC1), an intermediate filament–binding protein. Fine linked pure familial spastic paraparesis: characterization of mapping the SPG8 locus and construction of a physical a large kindred with magnetic resonance imaging studies. map across this locus will permit assessment of these Arch Neurol 52:665–669 Cartlidge NE, Bone G (1973) Sphincter involvement in hered- genes, as well as identification and analysis of other po- itary spastic paraplegia. Neurology 23:1160–1163 tential SPG8 candidate genes. Identification of genetic Casari G, Fusco M, Ciarmatori S, Zeviani M, Mora M, Fer- mutations responsible for autosomal dominant HSP will nandez P, DeMichele G, et al (1998) Spastic paraplegia and provide insight into the pathophysiology of this condi- OXPHOS impairment caused by mutations in paraplegin, tion and, it is hoped, into other inherited and degener- a nuclear-encoded mitochondrial metalloprotease. Cell 93: ative brain and spinal-cord disorders characterized by 973–983 axonal degeneration. De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, Monticelli A, et al (1998) A new locus for autosomal recessive hereditary spastic paraplegia maps to Acknowledgments chromosome 16q24.3. Am J Hum Genet 63:135–139 Dube M-P, Boutros M, Figlewicz DA, Rouleau GA (1997) A P.H. is supported by National Institutes of Health (NIH) new pure hereditary spastic paraplegia kindred maps to the training grant T32NS07222 and by a grant from the Campbell proteolipid protein gene locus. Am J Hum Genet Suppl 61: Family Foundation. This research is supported by grants A169 from the Muscular Dystrophy Association, by National In- Figlewicz DA, Dube MP, Farlow MR, Ebers G, Harper P, Ko- stitute of Neurological Disorders and Stroke (NIH), grants lodny EH, Baumbach L, et al (1994) Autosomal dominant R01NS33645 and R01NS36177, and by a Veterans Affairs familial spastic paraplegia: linkage analysis and evidence for Merit Review Award (all to J.K.F.). We gratefully acknowledge linkage to chromosome 2p. Am J Hum Genet Suppl 55:A185 the support of the Technology Access Section of the Utah Cen- Fink JK (1997) Advances in hereditary spastic paraplegia. Curr ter for Research; the technical assistance of Opin Neurol 10:313–318 Ms. Kara Bui and Ms. Cynthia Jaynes; the coordination of Fink JK, Heiman-Patterson T, Bird T, Cambi F, Dube´ M-P, genetic studies, by Joan Mathay, R.N.; and the expert secre- Figlewicz DA, Haines JL, et al (1996) Hereditary spastic tarial assistance of Ms. Lynette Girbach. We are grateful for paraplegia: advances in genetic research. Neurology 46: the participation of HSP patients and their family members, 1507–1514 without whom this research would not be possible. Fink JK, Sharp G, Lange B, Wu C-TB, Haley T, Otterud B, Peacock M, et al (1995a) Autosomal dominant hereditary Electronic-Database Information spastic paraparesis, type I: clinical and genetic analysis of a large North American family. Neurology 45:325–331 Accession numbers and URLs for data in this article are as Fink JK, Wu C-TB, Jones SM, Sharp GB, Lange BM, Lesicki follows: A, Reinglass T, et al (1995b) Autosomal dominant familial Hedera et al.: Hereditary Spastic Paraplegia on 8q 569

spastic paraplegia: tight linkage to chromosome 15q. Am J Nance MA, Raabe WA, Midani H, Kolodny EH, David WS, Hum Genet 56:188–192 Megna L, Pericak-Vance MA, et al (1998) Clinical hetero- Gispert S, Santos N, Damen R, Voit T, Schulz J, Klockgether geneity of familial spastic paraplegia linked to chromosome T, Orozco G, et al (1995) Autosomal dominant familial spas- 2p21. Hum Hered 48:169–178 tic paraplegia: reduction of the FSP1 candidate region on Nielsen JE, Jensen S, Jennum P, Koefoed P, Neerup Jensen L, chromosome 14q to 7 cM and locus heterogeneity. Am J Fenger K, Eiberg H, et al (1998) Autosomal dominant pure Hum Genet 56:183–187 spastic paraplegia: a clinical, paraclinical, and genetic study. Harding AE (1993) Hereditary spastic paraplegias. Semin Neu- J Neurol Neurosurg Psychiatry 64:61–66 rol 13:333–336 Nielsen JE, Koefoed P, Abell K, Hasholt L, Eiberg H, Fenger Hazan J, Fontaine B, Bruyn RPM, Lamy C, Van Deutekom K, Niebuhr E, et al (1997) CAG repeat expansion in au- JCT, Rime CS, Durr A, et al (1994) Linkage of a new locus tosomal dominant pure spastic paraplegia linked to chro- for autosomal dominant familial spastic paraplegia to chro- mosome 2p21-p24. Hum Mol Genet 6:1811–1816 mosome 2p. Hum Mol Genet 3:1569–1573 NIH/CEPH Collaborative Mapping Group (1992) A compre- Hazan J, Lamy C, Melki J, Munnich A, de Recondo J, Weis- hensive genetic linkage map of the human genome. Science senbach J (1993) Autosomal dominant familial spastic par- 258:67–86 aplegia is genetically heterogeneous and one locus maps to Philipp E (1949) Hereditary (familial) spastic paraplegia: re- chromosome 14q. Nat Genet 5:163–167 port of six cases in one family. NZ Med J 48:22–25 Hentati A, Pericak-Vance MA, Lennon F, Wasserman B, Hen- Polo JM, Calleja J, Combarris O, Berciano J (1993) Hereditary tati F, Juneja T, Angrist MH, et al (1994) Linkage of the “pure” spastic paraplegia: a study of nine families. J Neurol late onset autosomal dominant familial spastic paraplegia Neurosurg Psychiatry 56:175–181 to chromosome 2p markers. Hum Mol Genet 3:1867–1871 Rhein J (1914) Family spastic paralysis. J Nerv Ment Dis 44: Holmes G, Shaywitz B (1977) Strumpell’s pure familial spastic 115–144 paraplegia: case study and review of the literature. J Neurol Roe P (1963) Hereditary spastic paraplegia. J Neurol Neu- Neurosurg Psychiatry 40:1003–1008 rosurg Psychiatry 26:516–519 Keppen LD, Leppert MF, O’Connell P, Nakamura Y, Stauffer Scheltens P, Bruyn RPM, Hazenberg GJ (1990) A Dutch family D, Lathrop M, Lalouel J-M (1987) Etiological heteroge- neity in X-linked spastic paraplegia. Am J Hum Genet 41: with autosomal dominant pure spastic paraparesis (Strum- 933–943 pell’s disease). Acta Neurol Scand 82:169–173 Kobayashi H, Hoffman EP, Marks HG. (1994) The rump- Schwarz GA, Liu C-N (1956) Hereditary (familial) spastic shaker mutation in spastic paraplegia. Nat Genet 7:351–352 paraplegia: further clinical and pathologic observations. Lathrop GM, Lalouel JM, Julier C, Ott J (1985) Multipoint AMA Arch Neurol Psychiatry 75:144–162 linkage analysis in humans: detection of linkage and esti- Skre H (1974) Hereditary spastic paraplegia in western Nor- mation of recombination. Am J Hum Genet 37:482–498 way. Clin Genet 6:165–183 Lennon F, Gaskell PC, Woopert C, Aylsworth AS, Malin D, Sutherland JM (1975) Familial spastic paraplegia. In: Vinken Warner C, Farrell CD, et al (1995) Linkage and heteroge- PJ, Bruyn GW. Handbook of clinical neurology. Vol 22: neity in hereditary spastic paraparesis. Am J Hum Genet System disorders and atrophies. part II. North-Holland, Am- Suppl 57:A217 sterdam, pp 420–431 McKusick VA (1988) Spastic paraplegia, hereditary. In: Zatz M, Penha-Serrano C, Otto PA (1976) X-linked recessive McKusick VA. Mendelian inheritance in man. Johns Hop- type of pure spastic paraplegia in a large pedigree: absence kins University Press, Baltimore, p 1189 of detectable linkage with Xg. J Med Genet 13:217–222